With the introduction of highly active anti-retroviral therapy (HAART) in 1996, the typical cachexia associated with AIDS has fallen sharply, and the development of a new metabolic condition called “the lipodystrophy syndrome” has occurred. This new metabolic syndrome which affects HIV-infected patients receiving triple HAART was first described only recently, and is thought to be either an extension of the cachexia state or an adverse effect of the HAART treatment.
The main clinical features of the lipodystrophy syndrome are peripheral fat loss, central fat accumulation and metabolic abnormalities which lead to lactoacidosis. The overall incidence of these physical abnormalities in recent reports and in abstracts presented at 1999 AIDS meetings is about 50% after 12–18 months of therapy. The differences between these prevalence rates range from 18% to 83% due to confounding factors such as type and duration of anti-retroviral therapy and the lack of an objective and validated case definition.
The metabolic features associated with lipodystrophy and protease-inhibitor therapy include hypertriglyceridaemia, hypercholesterolaemia, insulin-resistance, type II diabetes mellitus and lactoacidosis. Dyslipidaemia at concentrations associated with increased cardiovascular disease occurs has been reported in about 70% of HIV patients receiving HAART. These metabolic abnormalities are more profound in those patients whose HAART regimen includes a protease inhibitor. More recently, peripheral fat loss has also been associated with low-grade lactic acidaemia liver dysfunction, but in the absence of lipid or glycaemic changes.
The metabolic changes of lipodystrophy may have serious clinical consequences. Several reports have described premature coronary-artery disease in patients with few or no risk factors that were receiving protease inhibitors. The increase in risk has been estimated from available metabolic data to be 1.4 cardiac events per 1000 patient-years.
It has been suggested that the lipodystrophy syndrome associated with protease inhibitors may be due to partial analogy between lipid and adipocyte regulatory proteins and the catalytic site of HIV-1 protease to which these protease inhibitors bind (Carr et al, Lancet 1998; 351:1881–83). In vitro studies have shown that protease inhibitors can inhibit lipogenesis (Zhang et al, J. Clin. Endocrinol. Metab. 1999; 84:4274–77, and Lenhard et al, Biochem Pharmacol 2000; 59:1063–68).
More recently, some features of this syndrome have been suggested to represent mitochondrial toxicity of nucleotide analogue reverse transcriptase inhibitors (NRTIs). Peripheral lipoatrophy with fat redistribution in association with hyperlactaemia has been reported in patients who received only NRTIs. These changes also occur in HIV-uninfected patients with mitochondrial defects.
The results from a study investigating the underlying effect of HIV-1 on metabolic and body composition parameters concluded that the metabolic abnormalities of the HAART-associated lipodystrophy syndrome may be related to the HIV-1 infectious process or to factors associated with immunological dysfunction (Shikuma et al, AIDS 1999; 13:1359–65). Another study of HIV-positive subjects receiving HAART revealed that lipodystrophy may result from the accumulation of T cells with impaired apoptosis, which are primed for TNF alpha synthesis (Ledru et al, Blood 2000; 95(10):3191–8). Protease inhibitors themselves have also been shown to impair T cell apoptosis (Sloand et al, Blood 1999; 94(3):1021–7).
The renin-angiotensin system (RAS) and its components are known and may be described as follows. Briefly, cells of the renal juxta-glomerular apparatus produce the aspartyl protease renin which acts on the alpha-2 globulin angiotensinogen (synthesised in the liver) to generate angiotensin I (AI). This non-pressor decapeptide is converted to angiotensin II (ATII) by contact with the peptidyldipeptidase angiotensin-converting enzyme (ACE). ATII stimulates the release of aldosterone, and is also a potent vasoconstrictor. The renin-angiotensin system is therefore important in the maintenance and control of blood pressure as well as the regulation of salt and water metabolism. Renin, angiotensinogen and ACE have also been identified in cardiovascular tissues including the heart and blood vessels, as has mRNA for components of this system such as angiotensinogen. Receptors for angiotensin II have been found on vascular smooth muscle cells. Within tissues, the RAS may therefore have a local paracrine function, and the expression of the different components can be altered by pathophysiological stimuli such as sodium restriction. Kinetic studies suggest that much of the circulating angiotensin I and II is derived from the both renal and non-renal tissues.
There are many marketed or investigation-stage agents which inhibit RAS activity, and many of them fall into two broad classes: inhibitors of angiotensin-converting enzyme, whose approved names generally end in “pril” or in the case of active metabolites “prilat”, and antagonists at angiotensin receptors (more specifically, currently, the AT1 receptor), whose approved names generally end in “sartan”. Also potentially of increasing importance may be a class of drugs known as neutral endopeptidase inhibitors, some of which will also have an ACE-inhibitory effect or the potential to reduce RAS activity.
WO 99/20268 discloses that ACE inhibitors can enhance the performance of those undergoing exercise, and suggests various therapeutic uses for such compounds, including the treatment of cachexia.